Dataset Information

Human skeletal muscle CD90⁺ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients.

ABSTRACT: Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle function and degeneration of the skeletal muscles. However, the mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscle of T2DM patients exhibit degenerative remodeling of the extracellular matrix that is associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90)-the FAP^CD90+. We identify platelet-derived growth factor (PDGF) as a key FAP regulator, as it promotes proliferation and collagen production at the expense of adipogenesis. FAPs^CD90+ display a PDGF-mimetic phenotype, with high proliferative activity, clonogenicity, and production of extracellular matrix. FAP^CD90+ proliferation was reduced by in vitro treatment with metformin. Furthermore, metformin treatment reduced FAP content in T2DM patients. These data identify a PDGF-driven conversion of a subpopulation of FAPs as a key event in the fibrosis development in T2DM muscle.

SUBMITTER: Farup J

PROVIDER: S-EPMC9165662 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Human skeletal muscle CD90<sup>+</sup> fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients.

Farup Jean J Just Jesper J de Paoli Frank F Lin Lin L Jensen Jonas Brorson JB Billeskov Tine T Roman Ines Sanchez IS Cömert Cagla C Møller Andreas Buch AB Madaro Luca L Groppa Elena E Fred Rikard Göran RG Kampmann Ulla U Gormsen Lars C LC Pedersen Steen B SB Bross Peter P Stevnsner Tinna T Eldrup Nikolaj N Pers Tune H TH Rossi Fabio M V FMV Puri Pier Lorenzo PL Jessen Niels N

Cell metabolism 20211021 11

Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle function and degeneration of the skeletal muscles. However, the mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscle of T2DM patients exhibit degenerative remodeling of the extracellular matrix that is associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90)-the FAP<sup>CD90+</sup ...[more]

PMID: 34678202

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Project description:Chronic muscle injuries, such as massive rotator cuff tears, are associated with progressive muscle wasting, fibrotic scarring, and intramuscular fat accumulation. While progenitor cell subsets are usually studied in culture conditions that drive either myogenic, fibrogenic, or adipogenic differentiation, it is still unknown how combined myo-fibro-adipogenic signals, which are expected to occur in vivo, modulate progenitor differentiation. We therefore evaluated the differentiation potential of retrospectively generated subsets of primary human muscle mesenchymal progenitors in multiplexed conditions in the presence or absence of 423F drug, a modulator of gp130 signaling. We identified a novel CD90+CD56- non-adipogenic progenitor subset that maintained a lack of adipogenic potential in single and multiplexed myo-fibro-adipogenic culture conditions. CD90-CD56- demarcated fibro-adipogenic progenitors (FAP) and CD56+CD90+ progenitors were typified as myogenic. These human muscle subsets exhibited varying degrees of intrinsically regulated differentiation in single and mixed induction cultures. Modulation of gp130 signaling via 423F drug mediated muscle progenitor differentiation in a dose-, induction-, and cell subset-dependent manner and markedly decreased fibro-adipogenesis of CD90-CD56- FAP. Conversely, 423F promoted myogenesis of CD56+CD90+ myogenic subset, indicated by increased myotube diameter and number of nuclei per myotube. 423F treatment eliminated FAP-derived mature adipocytes from mixed adipocytes-FAP cultures but did not modify the growth of non-differentiated FAP in these cultures. Collectively, these data demonstrate that capability of myogenic, fibrogenic, or adipogenic differentiation is largely dependent on the intrinsic features of cultured subsets, and that the degree of lineage differentiation varies when signals are multiplexed. Moreover, our tests performed in primary human muscle cultures reveal and confirm the potential triple-therapeutic effects of 423F drug which simultaneously attenuates degenerative fibrosis, fat accumulation and promotes myo-regeneration.

Dataset Information

Human skeletal muscle CD90⁺ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients.

Publications

Human skeletal muscle CD90<sup>+</sup> fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients.

Publications

Human skeletal muscle CD90<sup>+</sup> fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Human skeletal muscle CD90⁺ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients.